MARCH9, a potential target for the treatment of acute pancreatitis, inhibits NLRP3 inflammasome mediated pyroptosis

Abstract

Purpose: To investigate the regulatory mechanism of membrane associated ring-CH-type finger 9 (MARCH9) in acute pancreatitis (AP). Methods: Fifteen AP patients admitted in Changzhou Second People's Hospital Nanjing, China and fifteen healthy individuals participated in this study. MARCH9 expression in serum samples taken from the subjects was assayed. To establish an AP cell model, rat pancreatic acinar (PA) cells were induced with ceruletide and then transfected with MARCH9 overexpression vector. The MARCH9 level and molecular structure, which are related to pyroptosis and inflammatory cytokines, were determined. Cell survival rate and caspase 1 activity was assessed. Results: MARCH9 was lowly expressed in AP patients’ serum and in ceruletide-induced PA cells. Overexpression of MARCH9 enhanced the survival rate of ceruletide-induced PA cells and reduced the levels of inflammatory cytokines and molecules associated with pyroptosis. MARCH9 overexpression led to a decrease in caspase 1 activity in ceruletide-induced PA cells. Additionally, the overexpression of MARCH9 had a negative regulatory effect on the levels of IL6, p-STAT3/STAT3 and p-JAK2/JAK2 in PA cells induced by ceruletide. Conclusion: Overexpression of MARCH9 suppresses NLRP3-induced pyroptosis in PA cells through the regulation of IL6/JAK/STAT3 pathway, thus offerimg insights for the potential management of AP.